Dextran sulfate sodium enhances interleukin-1β release via activation of p38 MAPK and ERK1/2 pathways in murine peritoneal macrophages
Dextran sulfate sodium enhances interleukin-1β release via activation of p38 MAPK and ERK1/2 pathways in murine peritoneal macrophages
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DOI：
10.1016/j.lfs.2007.05.022
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发表时间：
2007-07-12
期刊：
影响因子：
6.1
通讯作者：
Murakami, Akira
中科院分区：
文献类型：
--
作者：
Kwon, Ki Han;Ohigashi, Hajime;Murakami, Akira
白介素1β(IL-1β)是一种促炎细胞因子，在炎症性肠病(IBD)的发病中起关键作用，但其产生的分子机制尚不完全清楚。我们研究了葡聚糖硫酸钠(DSS)诱导小鼠腹膜巨噬细胞(PM Empty Set)产生IL-1β和caspase-1活性。用Western blotting检测p38丝裂原活化蛋白激酶(MAPK)、细胞外信号调节激酶1/2(ERK1/2)和c-Jun氨基末端激酶(JNK1/2)及其上游靶蛋白的激活状态。RT-PCR法检测CXC趋化因子配体16(CXCL16)蛋白的表达。DSS处理的PMEmpty SET在3-24 h内以时间依赖的方式释放IL-1β蛋白，而不影响其mRNA水平，caspase-1活性在5分钟达到峰值(29倍)。DSS诱导的IL-1β释放和caspase-1活性可被MAPK 1/2抑制剂、p38 MAPK抑制剂和NAC显著抑制，但不能被JNK1/2或蛋白激酶C抑制剂所抑制。此外，DSS在2min和10min内分别显著诱导p38MAPK和ERK1/2的磷酸化。DSS还诱导细胞内产生活性氧(ROS)。抗CXCL16抗体可显著抑制DSS诱导的IL-1β的产生，而抗清道夫受体A、抗CD36或抗CD68抗体则不能显著抑制DSS诱导的IL-1β产生。我们的结果表明，DSS通过与CXCL16结合，产生ROS，从而激活p38MAPK和ERK1/2通路，最终激活caspase-1，从而在翻译后水平触发小鼠pMEmpty SET释放IL-1β蛋白。(C)2007 Elsevier Inc.保留所有权利。
Interleukin (IL)-1 beta is a pro-inflammatory cytokine that has been shown to play a pivotal role in the onset of inflammatory bowel disease (IBD), however, the molecular mechanisms underlying the production of IL-1 beta in IBD are not fully understood. We investigated dextran sulfate sodium (DSS)-induced IL-1 beta production and caspase-1 activities in murine peritoneal macrophages (pMempty set). Further, the activation status of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun NH2-terminal kinase (JNK1/2), as well as their upstream target kinases, were examined by Western blotting. In addition, mRNA expression was assessed by RT-PCR and CXC chemokine ligand 16 (CXCL16) protein was detected by immunocytochemistry. DSS-treated pMempty set released IL-1 beta protein in a time-dependent manner without affecting mRNA levels during 3-24 h, and caspase-1 activity peaked at 5 min (29-fold). IL-1 beta release and caspase-1 activity induced by DSS were significantly inhibited by a MAPK kinase 1/2 inhibitor, a p38 MAPK inhibitor, and NAC, however, not by JNK1/2 or a protein kinase C inhibitor. In addition, DSS strikingly induced the phosphorylation of p38 MAPK and ERK1/2 within 2 and 10 min, respectively. DSS also induced intracellular generation of reactive oxygen species (ROS). Pre-treatment with anti-CXCL16 for 24 h, but not anti-scavenger receptor-A, anti-CD36, or anti-CD68 antibodies, significantly suppressed DSS-induced IL-1 beta production. Our results suggest that DSS triggers the release of IL-1 beta protein from murine pMempty set at a post-translational level through binding with CXCL16, ROS generation, and resultant activation of both p38 MAPK and ERK1/2 pathways, and finally caspase-1 activation. (c) 2007 Elsevier Inc. All rights reserved.